Various pathological conditions are characterized by the attack of microbes on body tissues, resulting in local inflammation and the appearance of lesions characterized by tissue destruction at the infection site. The result of the accumulated tissue destruction may be a characteristic cavity or gap in the tissue, which may become enlarged as the infection and inflammation progresses.
Periodontal disease, in particular, is characterized by this course. Periodontal diseases comprise the various pathological conditions which are clinically and histologically detectable as inflammation of the periodontal tissues. The latter are collectively comprised of the gingiva, cementum, periodontal ligament, and alveolar bone. Periodontal diseases are caused by bacterial colonization of the surfaces of the teeth, and may be complicated by other hosts and causative factors. The disease is common in humans as well as in animals. Untreated periodontal disease causes loss of teeth which compromises the integrity and function of the masticatory system.
It is well documented that the progression of periodontal disease through various stages of severity begins with an accumulation of bacteria, termed plaque, on the tooth surface in the marginal area of the gingiva. See, for example, Rateitschak et al., Color Atlas of Periodontology (1985). The response to this formation of microbial plaque is an inflammation of the gingiva and the resulting breakdown of tissues, which causes the formation of an opening along the tooth surface known as the "periodontal pocket". As the bacterial colonization of the pocket and the inflammatory processes continue, the destruction of the periodontal tissues progresses and the tooth becomes loose. Once deprived of supporting tissues, which will not regenerate, the tooth will eventually be lost. The infection is local. The same patient may have entirely healthy teeth immediately proximal to the diseased tooth.
One treatment for removing periodontal disease aims to remove the bacteria from the tooth's surface and the pockets by mechanical means. Using various instruments such as curettes, sickles, hoes, files, etc., the bacteria are removed from the infected areas by scraping the teeth and pockets, one by one. Such mechanical procedures are very time consuming. Each tooth takes about 5-15 minutes to treat. The discomfort and pain for the patient are considerable. Mechanical removal of bacteria is a method of therapy which requires highly skilled dental operators. The procedure may be difficult to perform, particularly if the pockets are deep, and are presented with root fissures or furcations. In order to improve mechanical removal, the accessibility and visibility of the root surface may be facilitated by surgical procedures such as flap operations.
Since bacteria are involved in the etiology and progression of periodontal disease, antibacterial drugs have also been utilized in periodontal therapy. An effective concentration of an antibacterial drug at the site of infection may be achieved by the systemic administration of a high dosage of the drug. In order to maintain an effective concentration over an extended period of time, it is necessary to repeat the dosage 2-3 times daily for several weeks. Long term exposure to high dosages of antibiotics is associated with a high risk of side effects, a fact that has seriously limited the use of this treatment in periodontal therapy.
A better way to obtain an effective drug concentration at the site of infection is to apply the drug directly to the periodontal pocket. According to this methodology, only the amount of drug locally required is administered. The total dosage of the drug is thus reduced considerably. However, in order to maintain an effective concentration of drug for an extended period of time (days to weeks), the drug-containing system must be retained within the pocket, and the drug must be released slowly therefrom.
Delivery systems for controlled release of drugs into the periodontal pocket fall generally within two catagories: (1) solid drug-containing devices which are inserted into the pocket, or (2) thermodynamically unstable, fluid systems such as suspensions, emulsions, vesicles, and the like which are delivered into the pocket through fine tubings, such as needles and the like.
Examples of the solid drug-containing category of devices are the tetracycline-filled, hollow fibers that are tied around the tooth and pressed down below the gingiva. Such systems are described, for example, in Goodson et al., J. Clin. Periodon. 6, 83-92 (1979); Lindhe et al., J. Clin. Periodon. 6, 141-149 (1979); and Dunn et al. Proceed. Intern. Symp. Control Rel. Bioact. Mater. 14, 259-260 (1987). Other types of solid drug-containing devices comprise strips formed of drug-containing polymeric materials which are cut into shape and placed into the pocket, with, for example, tweezers: Addy et al., J. Periodontol. 53, 693-699 (1982); Golomb et al., J. Dent. Res. 63, 1149-1153 (1984); U.S. Pat. No. 4,568,535; and Minabe et al., J. Clin. Periodont. 16, 291-294 (1989). Such devices are difficult to manipulate, and may be lost accidentally during normal oral functions. Their insertion is timeconsuming, and the presence of a foreign body may induce or aggravate inflammatory processes.
Fluid periodontal delivery systems are described by Baker et al., Proceed. Intern. Symp. Control Rel. Bioact. Mater. 15, 238a-238b (1988) and European Patent Application 244,118 (1987). Microparticles are produced by dispersing or coating the drug with a release-controlling polymer. The microparticles are then suspended in a paste or gel and placed in the periodontal pocket with a syringe and rubber tube. One of the drawbacks of such systems is the limited shelf life due to the leaking of the drug from the particles once they are suspended in the carrier medium. Another disadvantage is the poor retention of the suspension within the periodontal pocket for a period of time long enough to result in successful treatment. The flow of gingival exudate in the inflamed pocket is considerable, and tends to wash away such particles.
A unique controlled-release preparation for delivery of biologically active materials has been proposed in European Patent Specification 126,751 B1. According to the invention described therein, a biologically active material is provided in mixture with an amphiphilic substance capable of forming a cubic or other type of liquid crystal-line phase when placed in contact with a liquid selected from the group of water, glycerol, ethylene glycol and propylene glycol. The cubic liquid crystalline phase is characterized as a thermodynamically stable, viscous and optically isotropic phase formed of the amphiphilic substance and water. The cubic phase may be unambiguously identified from the X-ray diffraction pattern. Other liquid crystalline phases, such as the hexagonal and reverse hexagonal phase, may be formed which, like the cubic phase, are described as being useful for drug delivery. The bioactive material is dissolved or dispersed in the liquid crystalline phase composed of water and the amphiphilic compound.
While the invention described in the aforesaid European Patent Specification represents an advance in the state of the art of controlled release delivery, such compositions have not been heretofore utilized for the formation of controlled release matrixes in situ at body sites, nor have they been used for the treatment of periodontal disease.